This Center proposes research concerning the pathogenesis of human nephrolithiasis (NL), a disease affecting millions of people in youth as well as adult life. The four investigators presently collaborate, and share two unique resources: a large population of well studied patients with NL, from which special groups of study subjects can be readily recruited into research protocols, and a colony of inbred rats that express a syndrome akin to human idiopathic hypercalciuria (IH). The rats form calcium stones in their kidneys and urinary tracts. In humans, IH accounts for over 50% of the remedial disorders that cause NL; we propose to investigate the pathophysiology of hypercalciuria and bone mineral dynamics in IH using both human subjects and the IH rats. The rats are hypercalciuric because their intestinal cells express an increased number of vitamin D receptors (VDR) that facilitates high calcium absorption despite normal serum levels of calcitriol. This is the first clue to mechanisms of. IH that could link the syndrome to abnormalities of gene expression. Not rarely, humans with IH absorb calcium at high rates yet have normal serum calcitriol levels. Thus we propose to study such patients asking if they, like the rats, have elevated VDR levels as a basis for hypercalciuria. Kidney cells produce potent inhibitors of the formation and growth of calcium oxalate crystals, which comprise the bulk of human stones. Among these are nephrocalcin, Tamm-Horsfall protein (THP) and uropontin. We have identified a number of patients with severe NL unexplained by well established metabolic causes, and propose to determine if dysfunctional urine inhibitors cause their stones. Once found among such highly selected patients, defects can be defined at a molecular level, and searched for among typical patients with NL. A key step in stone formation may be anchoring of crystals in tubular fluid to cells along the nephron so that microscopic ionic nuclei can attain sufficient size to become clinically important. Calcium oxalate crystals adhere to renal epithelial cells and undergo endocytosis, a sequence of events that is blocked by urinary THP from normal individuals but not from patients with accelerated NL. By defining mechanisms of crystal adherence and uptake we plan to identify the regulatory role of THP in cell-crystal interactions, and search for steps in the cellular response to crystals that are accessible to manipulation through drugs or other agents in order to hinder crystal attachment and prevent formation of stones.